The overarching goal of this application for an Independent Scientist Award is to improve the pharmacotherapy of late-life mental disorders. Inter-individual differences in drug oxidation are the most important cause of the wide range in drug concentrations which affect clinical response in older patients. The candidate proposes to incorporate recent advances in molecular pharmacogenetics and in vitro drug metabolism into his ongoing program of research on geriatric drug metabolism. This program currently utilizes cytochrome P450 isoenzyme-specific metabolic probes for GYPs 2D6, 2C19, 1A2 and 3A4, in conjunction with analyses for drug concentrations, active metabolites, and enantiomers. New initiatives in positron emission tomography will be integrated with ongoing appraisal of peripheral serotonergic and cholinergic receptor indices and sensitive quantitative outcome measures of cognition, behavioral disturbance, balance and motor function. This research plan is conducted within the framework of comparative trials of conventional and experimental medications for the two major psychiatric problems of old age, depression and dementia-associated behavioral disturbance. Study One (MH55106) is an ongoing, trial of citalopram, perphenazine and placebo for the treatment of behavioral disturbances associated with dementia in 112 patients. Study Two (MH52247) is an ongoing, comparative study of the cognitive and antidepressant effects of paroxetine and nortriptyline in 120 patients aged 60 years and older suffering from major depression. Study Three (Women's Health Supplement to MH52247) is a pilot examination of the P450 isozyme-specific effects of estrogen replacement therapy in 40 post menopausal women with mild to moderate depression. The long-term goal of the candidate's research is to derive and validate methods for prospective selection of specific psychotropics and their dosages for older patients, in the presence of intensely heterogeneous pharmacodynamics and drug metabolism caused by the combined effects of genetic polymorphism, changes associated with age or illness, and drug-induced inhibition or induction.